The present disclosure relates to tissue constructs and microscale platforms for their fabrication. More particularly, the present disclosure relates to cardiac tissue constructs, and applications thereof in screening.
Drug- and cell-based strategies for treating heart disease, including myocardial infarction, face significant roadblocks on the path to the clinic, a primary obstacle being the lack of information-rich in vitro human model systems. Conventional model systems are hampered by at least one of three fundamental limitations which include 1) the lack of a mature in vivo-like microenvironment specifically engineered for the input cell population, 2) a relatively low-throughput assay, and 3) the low-content nature of output parameters.
Directed differentiation strategies for generating and preserving human pluripotent stem cell (hPSC)-derived cardiomyocytes in scaled-up quantities are capable of efficiencies greater than 90% [1-7]. Additionally, several cell surface markers for cardiomyocytes have been discovered which can be used to sort out purified populations of interest using combinations of appropriate antibodies [8, 9]. Along with the recent advances in induced Pluripotent Stem Cell (iPSC) technology, one now has the ability to derive patient-specific cardiomyocytes on demand without lack in cell quantity. Despite these advances in scale-up of cardiomyocyte production and improvements in methods of purification and preservation, there is much needed work to be done in developing suitable methods of effectively using these target cells in a clinically useful manner.
One such area of value is in developing physiologically relevant in vitro model platforms for cardiac toxicity and drug screening. Although inducing hPSC to differentiate into contracting cardiomyocytes is an established technique, the maturation stage of these cells lack severely in comparison to adult cardiomyocytes [5]. Conventionally, hPSC-derived cardiomyocytes are used at early stages of differentiation, and cultured without supporting cells on two-dimensional stiff surfaces that 1) do not mimic the native heart microenvironment and 2) are not amenable to measuring appropriate parameters which can be linked to cardiac physiology (such as impulse propagation, conduction velocity, and force of contraction).